DGAT1 mutation is linked to a congenital diarrheal disorder

Abstract

Congenital diarrheal disorders (CDDs) are a collection of rare, heterogeneous enteropathies with early onset and often severe outcomes. Here, we report a family of Ashkenazi Jewish descent, with 2 out of 3 children affected by CDD. Both affected children presented 3 days after birth with severe, intractable diarrhea. One child died from complications at age 17 months. The second child showed marked improvement, with resolution of most symptoms at 10 to 12 months of age. Using exome sequencing, we identified a rare splice site mutation in the DGAT1 gene and found that both affected children were homozygous carriers. Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. The precise cause of diarrhea is unknown, but we speculate that it relates to abnormal fat absorption and buildup of DGAT substrates in the intestinal mucosa. Our results identify DGAT1 loss-of-function mutations as a rare cause of CDDs. These findings prompt concern for DGAT1 inhibition in humans, which is being assessed for treating metabolic and other diseases.

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

“…Haas et al described a non-consanguineous AshkenaziJewish family in which two of three siblings were homozygous for a splice site mutation leading to exon 8 deletion associated with PLE, hypoalbuminemia, and early-onset diarrhea. 4 This is the second report of patients with DGAT1 mutations. All known DGAT1-deficient patients have manifested with earlyonset non-bloody watery diarrhea, unresponsiveness to soy-based or elemental formula, and had clinical, laboratory, and pathological findings consistent with PLE.…”

“…This splicing mutation causes skipping of whole exon 8 of DGAT1 that result in the in-frame deletion of 25 amino acids (p.Ala226_Arg250del) in the protein level. 4 Both parents, as well as two of the six unaffected siblings (male and female), were heterozygous for this mutation.…”

“…SNP arrays revealed 10 areas of homozygosity (Table 1); DGATI, associated with congenital diarrhea and PLE, 4 resided in one such area. Sanger sequencing identified a novel homozygous missense variant in exon 10 of DGAT1, NM_012079.4: c.884T4C (Figure 2a), which is predicted to lead to p.(Leu295Pro) in the protein level.…”

“…We estimated the prevalence of DGAT1 deficiency by combining the allele frequencies of all the loss-of-function variants, and all missense mutations predicted to be deleterious by both PolyPhen2 (Probably deleterious) and SIFT (Damaging) to~1-/300 000 ( Table 2). This translates to a frequency similar to that of a rare disease, but, as to date, only one family has been described; 4 thus, DGAT1 deficiency is an underdiagnosed disease.…”

“…3 Patients with biallelic mutations in DGAT1 (MIM #: 604900) manifest aspects of both PLE and CDD. 4 DGAT1 encodes a diacyl CoA:diacylglycerol acyl transferase (DGAT) that converts diacylglycerides to triglycerides (TGs) by adding an acyl CoA moiety. 5 The enzyme belongs to the family of membrane-bound O-acyl transferases (MBOATs), with its active domain located in the lumenal region of the endoplasmic reticulum (ER).…”